Reduced ?-cell mass and increased ?-cell apoptosis are key to the pathophysiology of both type 1 and type 2 diabetes. Therefore, identifying factors that can protect from ?-cell apoptosis will meet a critical thera- peutic need in the prevention and treatment of diabetes. Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) are peptide hormones normally produced in the intestine with beneficial effects on ?-cell mass and func- tion. Both GLP-1 and CCK are produced within the pancreatic islet under conditions of islet stress. GLP-1 based therapies are in widespread use for the treatment of type 2 diabetes, and there is substantial evidence in cell lines and rodent models that GLP-1 can protect from ?-cell apoptosis. Similarly, we have shown that CCK is necessary and sufficient to protect from ?-cell apoptosis in mouse models. While CCK has been widely studied in exocrine pancreatic cells, there is limited information about the role of CCK in the ?-cell. We propose that the production of these hormones in the islet represents a compensatory physiologic mechanism to pro- mote ?-cell survival. The long-term goal is to identify novel pathways critical in the preservation of ?-cell mass. The overall objective of this application is to determine the regulation of locally produced GLP-1 and CCK and their role in protection from ?-cell apoptosis. The central hypothesis is that an intra-islet signaling network ex- ists, whereby GLP-1 produced in the ?-cell and CCK produced in the ?-cell are co-regulated and work together to promote ?-cell survival. To achieve the objective, three Specific Aims are proposed. In Aim 1, we will deter- mine how GLP-1 and CCK production are regulated in the pancreatic islet. Preliminary evidence support the hypothesis that CCK and GLP-1 signal in a paracrine manner within the islet to co-regulate one another. We will use transgenic overexpression of ?-cell CCK and receptor knockout mouse models to clarify how these hormones regulate one another in the islet. In Aim 2, we will identify the mechanism of CCK-mediated protec- tion from cytokine-induced apoptosis. We will use receptor antagonists and knockouts to determine which CCK receptor regulates ?-cell survival and we will determine the intracellular signaling pathways activated by CCK in the ?-cell. In Aim 3, we will determine if GLP-1 and CCK can synergistically and interdependently protect human islets from apoptosis. We have intriguing evidence that the role of GLP-1 in ?-cell survival is dependent on CCK receptor signaling in a cell line. This suggests the innovative concept that the impact of GLP-1 on the ?-cell relies on its ability to stimulate CCK. As human islets have very different characteristics than mouse islet, examining the role of GLP-1 and CCK specifically in human islets is of critical importance to translation of our findings to diabetes therapies. These studies will contribute to our fundamental understanding of this novel in- tra-islet hormonal regulatory pathway and the mechanisms whereby GLP-1 and CCK promote ?-cell survival. This contribution is significant as it will advance knowledge of both adaptive and therapeutic mechanisms of ?- cell survival, allowing development of targeted therapies with maximal efficacy and minimal side effects.